Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.
Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.
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DOI：
10.1200/jco.22.00912
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发表时间：
2022-07-20
影响因子：
45.3
通讯作者：
Herbst, Roy S.
中科院分区：
文献类型：
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作者：
Reckamp, Karen L.;Redman, Mary W.;Dragnev, Konstantin H.;Minichiello, Katherine;Villaruz, Liza C.;Faller, Bryan;Al Baghdadi, Tareq;Hines, Susan;Everhart, Leah;Highleyman, Louise;Papadimitrakopoulou, Vassiliki;Gandara, David R.;Kelly, Karen;Herbst, Roy S.
晚期非小细胞肺癌（NSCLC）对免疫检查点抑制（ICI）的耐药性是一个主要的未满足需求。ICI与血管内皮生长因子（VEGF）/VEGF受体抑制剂的组合在多种肿瘤类型中产生了有希望的结果。在这项随机化II期肺MAP不匹配子研究（S1800 A）中，既往接受过ICI和含铂化疗且在ICI开始后至少84天出现疾病进展的NSCLC患者不符合生物标志物匹配子研究的条件，被随机分配接受雷莫芦单抗联合帕博利珠单抗（RP）或研究者选择的标准治疗（SOC：多西他赛/雷莫芦单抗、多西他赛、吉西他滨和培美曲塞）。目标为130例合格患者，主要目的是使用单侧10%水平，采用标准对数秩（SLR）和加权对数秩（WLR; G[rho = 0，gamma = 1]）检验中的较优者比较总生存期（OS）。次要终点包括客观缓解、缓解持续时间、评估者评估的无进展生存期和毒性。在入组的166例患者中，136例合格（69例RP; 67例SOC）。RP组OS显著改善（风险比[80% CI]：0.69 [0.51 - 0.92]; SLR单侧P = 0.05; WLR单侧P = 0.15）。RP和SOC的中位（80%CI）OS分别为14.5（13.9 - 16.1）个月和11.6（9.9 - 13.0）个月。在大多数亚组中观察到RP的OS获益。研究者评估的无进展生存期（风险比[80% CI]：0.86 [0.66 - 1.14];单侧SLR，WLR的P = 0.25和0.14）和缓解率（22% RP vs 28% SOC，单侧P = 0.19）在两组之间相似。RP组中42%的患者和SOC组中60%的患者发生≥ 3级治疗相关不良事件。这项随机II期试验表明，在既往接受ICI和化疗的晚期NSCLC患者中，RP组的OS较SOC组显著改善。安全性与两种药物的已知毒性一致。这些数据值得进一步评价。
Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.